The coupling of neural activity and increased blood flow (neurovascular coupling) is vital to brain function. Failure of this coupling occurs early in Alzheimer?s disease (AD) and ?pure? tauopathies and induces chronic brain injury, contributing to neurodegeneration.Amongothermediators,neurovascularcouplingisregulatedby nitric oxide (NO) bioavailability. NO formed by the neuronal form of nitric oxide synthase (nNOS) is central to neurovascular coupling, and its production by nNOS-expressing interneurons depends on microtubule- dependenttransportofnNOStodendrites.Tauprotein,causallyimplicatedinAD,stabilizesmicrotubules.Under pathologic conditions, hyperphosphorylated tau detaches from microtubules, destabilizing the microtubule cytoskeleton. Soluble hyperphosphorylated tau aggregates transfer trans-neuronally, promoting native tau phosphorylation and microtubule destabilization in target cells. Among the neuron types targeted by tau pathology in AD are vasculature-associated nNOS-expressing neurons. The functional impact of pathogenic tauonnNOSneurons,anditscontributiontobrainvasculardysfunctioninAD,havenotbeenexploredandare not understood. The objective of this proposal is to define mechanisms of pathogenic tau-induced brain vascular dysfunction and determine whether removing pathogenic tau with immunotherapy is a potential treatmentforAD.Wehypothesizethatsolubletauaggregatescriticallycontributetobrainvasculardysfunction in AD by blocking nNOS activation, and that removal of soluble tau aggregates with immunotherapy will prevent and potentially treat brain vascular dysfunction by restoring nNOS activity. Our studies show that aggregation-prone human tau causes neurovascular coupling deficits driven by reduced nNOS activation in modelsofADtauopathy;?andthattransmissionofsolubleaggregatedtauintoneuronsblocksnNOSactivation, suggestingthatpathogenictaudrivesbraindysfunctionbyimpairingnNOS.Wewilltestourcentralhypothesis by pursuing two Specific Aims. In Aim 1, we will define the mechanisms by which soluble tau aggregates impede nNOS activation using in vitro approaches, and identify molecular alterations triggered by tau aggregates in vivo in microvasculature-associated neurons during disease progression in a mouse model of AD tauopathy. In Aim 2, we will establish the therapeutic potential of soluble aggregated tau removal in AD cerebrovasculardysfunction,usingantibody-basedremovalofsolubletauaggregatesearlyinADprogression and after disease onset, and determine, in human AD brains, how accumulation of tau aggregates and molecular alterations identified in Aim 1 correlate with AD histopathology and progression. The role of tau in AD cerebrovascular dysfunction is unexplored. As a result of the work proposed, we expect to (a) identify solubletauaggregate-inducedmolecularalterationsthatdiminishnNOSactivity,(b)definetheimpactofnNOS impairment by soluble aggregated tau in cerebrovascular deficits of AD, and (c) evaluate whether tau immunotherapymayhavepromiseforAD.Theseresultsareexpectedtomarkedlyadvanceourunderstanding ofhowpathogenictau,andcellulareventsittriggers,canbetargetedfortherapeuticpurposes.Inaddition,this study will contribute novel insights into the role of tau in cerebrovascular dysfunction of AD and other tauopathies.Equallyimportant,theresultsofthisstudywillhaveapositiveimpactbecausetheidentificationof solubleaggregatedtauasadriverofADcerebrovasculardysfunctionwillrevealnoveltargetsfortherapiesand propelforwardnewresearchincerebrovascularbiologyandneurodegeneration.